Pyrazolo[3,4-c]pyridines as gsk-3 inhibitors

ABSTRACT

A compound of formula (I) or a derivative thereof, wherein R 1  is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, aralkyl wherein the aryl and the alkyl moieties may each independently be unsubstituted or substituted, aralkenyl wherein the aryl and alkenyl moieties may each independently be unsubstituted or substituted, unsubstituted or substituted heterocyclyl, or heterocyclyalkyl wherein the heterocyclyl and the alkyl moieties may each independently be unsubstituted or substituted; and R 2  is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds and composition in medicine.

[0001] This invention relates to novel compounds, in particular to novelpyrazolopyridine derivatives, to processes for the preparation of suchcompounds, to pharmaceutical compositions containing such compounds andto the use of such compounds in medicine.

[0002] GSK-3 is a serine/threonine protein kinase composed of twoisoforms (αand β) which are encoded by distinct genes. GSK-3 is one ofseveral protein kinases which phosphorylates glycogen synthase (GS)(Embi et al. Eur. J. Biochem. (107) 519-527 (1980)). The a and Pisoforms have a monomeric structure and are both found in mammaliancells. Both isoforms phosphorylate muscle glycogen synthase (Cross etal. Biochemical Journal (303) 21-26 (1994)) and these two isoforms showgood homology between species (e.g. human and rabbit GSK-3α are 96%identical).

[0003] Type II diabetes (or Non-Insulin Dependent Diabetes Mellitus,NIDDM) is a multifactorial disease. Hyperglycaemia is due to insulinresistance in the liver, muscle and other tissues coupled withinadequate or defective secretion of insulin from pancreatic islets.Skeletal muscle is the major site for insulin-stimulated glucose uptakeand in this tissue, glucose removed from the circulation is eithermetabolised through glycolysis and the TCA cycle, or stored as glycogen.Muscle glycogen deposition plays the more important role in glucosehomeostasis and Type II diabetic subjects have defective muscle glycogenstorage.

[0004] The stimulation of glycogen synthesis by insulin in skeletalmuscle results from the dephosphorylation and activation of glycogensynthase (Villar-Palasi C. and Larner J. Biochim. Biophys. Acta (39)171-173 (1960), Parker P J et al., Eur. J. Biochem. (130) 227-234(1983), and Cohen P. Biochem. Soc. Trans. (21) 555-567 (1993)). Thephosphorylation and dephosphorylation of GS are mediated by specifickinases and phosphatases. GSK-3 is responsible for phosphorylation anddeactivation of GS, while glycogen bound protein phosphatase 1 (PP1G)dephosphorylates and activates GS. Insulin both inactivates GSK-3 andactivates PP1G (Srivastava A K and Pandey S K Mol. and Cellular Biochem.(182) 135-141 (1998)).

[0005] Chen et al. Diabetes (43) 1234-1241 (1994) found that there wasno difference in the mRNA abundance of PP1G between patients with TypeII diabetes and control patients, suggesting that an increase in GSK-3activity might be important in Type II diabetes. It has also recentlybeen demonstrated that GSK-3 is overexpressed in Type II diabetic muscleand that an inverse correlation exists between skeletal muscle GSK-3αactivity and insulin action (Nikoulina et al. Diabetes 2000,49 263-271).Overexpression of GSK-3β and constitutively active GSK-3β (S9A, S9E)mutants in HEK-293 cells resulted in suppression of glycogen synthaseactivity (Eldar-Finkelman et al., PNAS (93) 10228-10233 (1996)) andoverexpression of GSK-3β in CHO cells, expressing both insulin receptorand insulin receptor substrate 1 (IRS-1), resulted in an impairment ofinsulin action (Eldar-Finkelman and Krebs PNAS (94) 9660-9664 (1997)).Recent evidence for the involvement of elevated GSK-3 activity and thedevelopment of insulin resistance and type II diabetes in adipose tissuehas emerged from studies undertaken in diabetes and obesity proneC57BL/6J mice (Eldar-Finkelman et al., Diabetes (48) 1662-1666 (1999)).

[0006] GSK-3 has been shown to phosphorylate other proteins in vitroincluding the eukaryotic initiation factor eIF-2B at Serine⁵⁴⁰ (Welsh etal., FEBS Letts (421) 125-130 (1998)). This phosphorylation results inan inhibition of eIF-2B activity and leads to a reduction in this keyregulatory step of translation. In disease states, such as diabetes,where there is elevated GSK-3 activity this could result in a reductionof translation and potentially contribute to the pathology of thedisease.

[0007] Several aspects of GSK-3 functions and regulation in addition tomodulation of glycogen synthase activity indicate that inhibitors ofthis enzyme may be effective in treatment of disorders of the centralnervous system. GSK-3 activity is subject to inhibitory phosphorylationby PI 3 kinase-mediated or Wnt-1 class-mediated signals that can bemimicked by treatment with lithium, a low mM inhibitor of GSK-3(Stambolic V., Ruel L. and Woodgett J. R. Curr. Biol. 1996 6(12):1664-8).

[0008] GSK-3 inhibitors may be of value as neuroprotectants in treatmentof acute stroke and other neurotraumatic injuries. Rôles for PI 3-kinasesignalling through PKB/akt to promote neuronal cell survival are wellestablished, and GSK-3 is one of a number of PKB/akt substrates to beidentified that can contribute to the inhibition of apoptosis via thispathway (Pap & Cooper, (1998) J. Biol. Chem. 273: 19929-19932). Evidencesuggests that astrocytic glycogen can provide an alternative energysource to facilitate neuronal survival under conditions of glucosedeprivation (for example see Ransom, B. R. and Fern, R. (1997) Glia 21:134-141 and references therein). Lithium is known to protect cerebellargranule neurons from death (D'Mello et al., (1994) Exp. Cell Res. 211:332-338 and Volonte et al. (1994) Neurosci. Letts. 172: 6-10) andchronic lithium treatment has demonstrable efficacy in the middlecerebral artery occlusion model of stroke in rodents (Nonaka and Chuang,(1998) Neuroreport 9(9): 2081-2084). Wnt-induced axonal spreading andbranching in neuronal culture models has been shown to correlate withGSK-3 inhibition (Lucas & Salinas, (1997) Dev. Biol. 192: 31-44)suggesting additional value of GSK-3 inhibitors in promoting neuronalregeneration following neurotraumatic insult.

[0009] Tau and β-catenin, two known in vivo substrates of GSK-3, are ofdirect relevance in consideration of further aspects of the value ofGSK-3 inhibitors in relation to treatment of chronic neurodegenerativeconditions. Tau hyperphosphorylation is an early event inneurodegenerative conditions such as Alzheimer's disease (AD), and ispostulated to promote microtubule disassembly. Lithium has been reportedto reduce the phosphorylation of tau, enhance the binding of tau tomicrotubules, and promote microtubule assembly through direct andreversible inhibition of glycogen synthase kinase-3 (Hong M., Chen D.C., Klein P. S. and Lee V. M. J.Biol. Chem. 1997 272(40) 25326-32).β-catenin is phosphorylated by GSK-3 as part of a tripartite complexwith axin, resulting in β-catenin being targeted for degradation (Ikedaet al., (1998) EMBO J. 17: 1371-1384). Inhibition of GSK-3 activity is akey mechanism by which cytosolic levels of catenin are stabilised andhence promote β-catenin-LEF-1/TCF transcriptional activity (Eastman,Grosschedl (1999) Curr. Opin. Cell Biol. 11: 233). Rapid onset ADmutations in presenilin-1 (PS-1) have been shown to decrease thecytosolic β-catenin pool in transgenic mice. Further evidence suggeststhat such a reduction in available β-catenin may increase neuronalsensitivity to amyloid mediated death through inhibition ofβ-catenin-LEF-1/TCF transcriptional regulation of neuroprotective genes(Zhang et al., (1998) Nature 395: 698-702). A likely mechanism issuggested by the finding that mutant PS-1protein confers decreasedinactivation of GSK-3 compared with normal PS-1 (Weihl, C. C., Ghadge,G. D., Kennedy, S. G., Hay, N., Miller, R. J. and Roos, R. P.(1999) J.Neurosci. 19: 5360-5369).

[0010] International Patent Application Publication Number WO 97/41854(University of Pennsylvania) discloses that an effective drug for thetreatment of manic depression is lithium, but that there are seriousdrawbacks associated with this treatment. Whilst the precise mechanismof action of this drug for treatment of manic depression remains to befully defined, current models suggest that inhibition of GSK-3 is arelevant target that contributes to the modulation of AP-1 DNA bindingactivity observed with this compound (see Manji et al., (1999) J. Clin.Psychiatry 60 (suppl 2): 27-39 for review).

[0011] GSK-3 inhibitors may also be of value in treatment ofschizophrenia. Reduced levels of β-catenin have been reported inschizophrenic patients (Cotter D, Kerwin R, al-Sarraji S, Brion J P,Chadwich A, Lovestone S, Anderton B, and Everall I. 1998 Neuroreport9:1379-1383 ) and defects in pre-pulse inhibition to startle responsehave been observed in schizophrenic patients (Swerdlow et al., (1994)Arch. Gen. Psychiat. 51: 139-154). Mice lacking the adaptor proteindishevelled-1, an essential mediator of Wnt-induced inhibition of GSK-3,exhibit both a behavioural disorder and defects in pre-pulse inhibitionto startle response (Lijam N, Paylor R, McDonald M P, Crawley J N, DengC X, Herrup K, Stevens K E, Maccaferri G, McBain C J, Sussman D J, andWynshaw-Boris A. (1997) Cell 90: 895-905). Together, these findingsimplicate deregulation of GSK-3 activity as contributing toschizophrenia. Hence, small molecule inhibitors of GSK-3 catalyticactivity may be effective in treatment of this mood disorder.

[0012] The finding that transient β-catenin stabilisation may play arole in hair development (Gat et al., Cell (95) 605-614(1998)) suggeststhat GSK-3 inhibitors could be used in the treatment of baldness.

[0013] Studies on fibroblasts from the GSK-3β knockout mouse (HoeflichKP et al., Nature 2000, 406, 86-90) support a role for this kinase inpositively regulating the activity of NFkB. This transcription factormediates cellular responses to a number of inflammatory stimuli.Therefore, pharmacologic inhibition of GSK-3 may be of use in treatinginflammatory disorders through the negative regulation of NFkB activity.

[0014] The compounds of the present invention arepyrazolo[3,4-c]pyridines. Other pyrazolo[3,4-c]pyridines have previouslybeen reported in the art. For example, U.S. Pat. No. 3,423,414 (B latteret al..) describes a series of pyrazolo[3,4-c]pyridines in which theC(7) position of the pyrazolopyridine ring is bisubstituted by H, alkylor a combination thereof, or in which the C(7) position is substitutedby an oxo group. The document provides no details regarding themechanism of action of these compounds, nor does it contain biologicaldata. It is suggested that such compounds have a potential therapeuticutility as anti-inflammatory agents.

[0015] We have now discovered that a series of pyrazolo[3,4-c]pyridinesare particularly potent and selective inhibitors of GSK-3. Thesecompounds are indicated to be useful for the treatment and/orprophylaxis of conditions associated with a need for inhibition ofGSK-3, such as diabetes, conditions associated with diabetes, chronicneurodegenerative conditions including dementias such as Alzheimer'sdisease, Parkinson's disease, progressive supranuclear palsy, subacutesclerosing panencephalitic parkinsonism, postencephalitic parkinsonism,pugilistic encephalitis, guam parkinsonism-dementia complex, Pick'sdisease, corticobasal degeneration, frontotemporal dementia,Huntingdon's disease, AIDS associated dementia, amyotrophic lateralsclerosis, multiple sclerosis and neurotraumatic diseases such as acutestroke, mood disorders such as schizophrenia and bipolar disorders,promotion of functional recovery post stroke, cerebral bleeding (forexample, due to solitary cerebral amyloid angiopathy), hair loss,obesity, atherosclerotic cardiovascular disease, hypertension,polycystic ovary syndrome, syndrome X, ischaemia, traumatic braininjury, cancer, leukopenia, Down's syndrome, Lewy body disease,inflammation, and immunodeficiency.

[0016] Accordingly, in a first aspect, the present invention provides acompound of formula (I)

[0017] or a derivative thereof,

[0018] wherein;

[0019] R¹ is unsubstituted or substituted alkyl, unsubstituted orsubstituted cycloalkyl, unsubstituted or substituted alkenyl,unsubstituted or substituted cycloalkenyl, unsubstituted or substitutedaryl, aralkyl wherein the aryl and the alkyl moieties may eachindependently be unsubstituted or substituted, aralkenyl wherein thearyl and alkenyl moieties may each independently be unsubstituted orsubstituted, unsubstituted or substituted heterocyclyl, orheterocyclylalkyl wherein the heterocyclyl and the alkyl moieties mayeach independently be unsubstituted or substituted; and

[0020] R² is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl.

[0021] In a preferred aspect, there is provided a compound of formula(I) or a derivative thereof wherein R¹ is unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl, orheterocyclylalkyl wherein the heterocyclyl and the alkyl moieties mayeach independently be unsubstituted or substituted; and wherein R² isunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl.

[0022] When R¹ is unsubstituted or substituted alkyl, examples includeC₁₋₆alkyl, for example methyl, ethyl, propyl, butyl and iso-propyl.

[0023] When R¹ is unsubstituted or substituted cycloalkyl, examplesinclude C₃₋₈cycloalkyl, for example cyclopropyl and cyclopentyl.

[0024] When R¹ is unsubstituted or substituted alkenyl, examples includeC₂₋₆alkenyl.

[0025] When R¹ is unsubstituted or substituted aryl, examples includephenyl.

[0026] When R¹ is unsubstituted or substituted aralkyl, examples includebenzyl and phenethyl.

[0027] When R¹ is unsubstituted or substituted aralkenyl, examplesinclude styryl.

[0028] When R¹ is unsubstituted or substituted heterocyclyl, examplesinclude fluryl, pyridyl and piperidinyl. Suitably R¹ is piperidinyl.

[0029] When R¹ is unsubstituted or substituted heterocyclylalkyl,examples include piperidinylpropyl, piperazinylpropyl,morpholinylpropyl, pyrrolidinylpropyl and pyridylethyl. Suitably, R¹ ispiperidinylpropyl, piperazinylpropyl and pyrrolidinylpropyl.

[0030] When R¹ is substituted alkyl, suitable substituents include halo,C₁₋₆alkoxy, carboxy, di(C₁₋₆alkyl)amino and phenoxy.

[0031] When R¹ is substituted aryl, suitable substituents include up tofive groups independently selected from the list consisting of hydroxy,C₁₋₆alkoxy, di(C₁₋₆alkyl)amino, cyano, C₁₋₆alkyl, carboxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, C₁₋₆alkylcarbonylamino,amino, halo, nitro and a subtituent —R³NR⁴R⁵ wherein R³ is C₁₋₆alkyleneand R⁴ and R⁵ are C₁₋₆alkyl, or R³ is C₁₋₆alkylene and R⁴ and R⁵together with the nitrogen atom to which they are attached form ahetrocyclic ring.

[0032] When R¹ is substituted heterocyclyl, suitable substituentsinclude up to five groups independently selected from the listconsisting of hydroxy, C₁₋₆alkoxy, di(C₁₋₆alkyl)amino, cyano, C₁₋₆alkyl,carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl,C₁₋₆alkylcarbonylamino, amino, halo, nitro and a subtituent —R³NR⁴R⁵wherein R³ is C₁₋₆ alkylene and R⁴ and R⁵ are C₁₋₆alkyl, or R³ isC₁₋₆alkylene and R⁴ and R⁵ together with the nitrogen atom to which theyare attached form a hetrocyclic ring.

[0033] Suitably, R¹ is n-propyl, iso-propyl, cyclopropyl, cyclopentyl,3-dimethylaminopropyl, 4-dimethylaminophenyl, 3-(pyrrolidin-1-yl)propyl,3-(piperidin-1-yl)propyl, 3-(4-ethylpiperazin-1-yl)propyl,1-methylpiperidin-4-yl and 4-[(pyrrolidin-1-yl)methyl]phenyl.

[0034] When R² is unsubstituted or substituted aryl, examples includephenyl.

[0035] When R² is unsubstituted or substituted heteroaryl, examplesinclude pyridinyl, thienyl, furyl, quinolinyl and indolyl. Suitably, R²is pyridin-3-yl or quinolin-3-yl.

[0036] When R² is substituted aryl, suitable substituents include up tofive groups independently selected from the list consisting ofbenzyloxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₃alkylenedioxy,C₁₋₆alkylcarbonylamino, perhaloC₁₋₆alkyl, nitro and perhaloC₁₋₆alkoxy.

[0037] When R² is substituted heteroaryl, suitable substituents includeup to five groups independently selected from the list consisting ofC₁₋₆alkoxy, halo, aryl and C₁₋₆alkyl. Suitably, R² is phenyl,2-chlorophenyl, 2,3-difluorophenyl, 4-fluorophenyl,2,3,4-trifluorophenyl, pyridin-3-yl, 5-phenylpyridin-3-yl,6-methylpyridin-3-yl, 6-methyoxypyridin-3-yl and quinolin-3-yl.

[0038] In a further preferred aspect, there is provided a subset ofcompounds of formula (I) of formula (IA),

[0039] or a derivative thereof,

[0040] wherein;

[0041] R¹ is C₁₋₆ alkyl, cycloC₃₋₈ alkyl, di(C₁₋₆ alkyl)aminoalkyl,phenyl optionally substituted by di(C₁₋₆ alkyl)amino, heterocyclylwherein the heterocyclyl moiety may be optionally substituted by C₁₋₆alkyl and heterocyclylC₁₋₆alkyl wherein the heterocyclyl moiety may beoptionally substituted by C₁₋₆ alkyl and phenyl; and

[0042] R² is phenyl optionally substituted by one or more halo atoms,quinolinyl and pyridinyl optionally susbtituted by C₁₋₆ alkyl, C₁₋₆alkoxy and phenyl.

[0043] In a further preferred aspect of the present invention there isprovided a subset of compounds of formula (I), wherein R¹ is n-propyl,iso-propyl, cyclopropyl, cyclopentyl, 3-dimethylaminopropyl,4-dimethylaminophenyl, 3-(pyrrolidin-1-yl)propyl,3-(piperidin-1-yl)propyl, 3-(4-ethylpiperazin- 1-yl)propyl,1-methylpiperidin-4-yl and 4-[(pyrrolidin-1yl)methyl]phenyl and whereinR² is as defined in formula (I).

[0044] In a further preferred aspect of the present invention there isprovided a subset of compounds of formula (I), wherein R¹ is as definedin formula (I) and wherein R² is phenyl, 2-chlorophenyl,2,3-difluorophenyl, 4-fluorophenyl, 2,3,4-trifluorophenyl, pyridin-3-yl,5-phenylpyridin-3-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl andquinolin-3-yl.

[0045] In still a further preferred aspect of the present inventionthere is provided a subset of compounds of formula (I), wherein R¹ isn-propyl, iso-propyl, cyclopropyl, cyclopentyl, 3-dimethylaminopropyl,4-dimethylaminophenyl, 3-(pyrrolidin-1-yl)propyl,3-(piperidin-1-yl)propyl, 3-(4-ethylpiperazin-1-yl)propyl,1-methylpiperidin4-yl and 4-[(pyrrolidin-1-yl)methyl]phenyl and whereinR² is phenyl, 2-chlorophenyl, 2,3-difluorophenyl, 4-fluorophenyl,2,3,4-trifluorophenyl, pyridin-3-yl, 5-phenylpyridin-3-yl,6-methylpyridin-3-yl, 6-methoxypyridin-3-yl and quinolin-3-yl.

[0046] Particularly preferred compounds of formula (I) which are ofspecial interest as agents useful in the treatment and/or prophylaxis ofconditions associated with a need for inhibition of GSK-3 are providedin Table 1 below.

[0047] Certain of the compounds of formula (I) may contain chiral atomsand/or multiple bonds, and hence may exist in one or more stereoisomericforms. The present invention encompasses all of the stereoisomeric formsof the compounds of formula (I) whether as individual stereoisomers oras mixtures of stereoisomers, including geometric isomers and racemicmodifications. Certain compounds of formula (I) may also exist astautomers. The present invention encompasses all of the tautomeric formsof the compounds of formula (I).

[0048] Alkyl groups referred to herein, including those forming part ofother groups, include straight or branched chain alkyl groups containingup to twelve, suitably up to six carbon atoms. These alkyl groups may beoptionally substituted with up to five, suitably up to three, groupsselected from the list consisting of aryl, heterocyclyl, alkylthio,alkenylthio, alkynylthio, arylthio, heterocyclylthio, alkoxy,arylalkoxy, arylalkylthio, amino, mono- or di-alkylamino, cycloalkyl,cycloalkenyl, carboxy and esters thereof, phosphonic acid and estersthereof, mono- or dialkylaminosulphonyl, aminosulphonyl, cyano,alkylcarbonylamino, arylcarbonylamino, arylaminocarbonyl,arylalkylaminocarbonyl, arylalkylcarbonylamino, thiazolidinedionyl,piperazinylcarbonyl wherein the piperazine may be unsubstituted orsubstituted, morpholinylcarbonyl, piperidinylcarbonyl,hydroxyalkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyl,dialkylaminoalkylaminocarbonyl, alkoxycarbonylamino,alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino,alkoxycarbonylalkylcarbonylamino, alkylaminocarbonyl, aminosulphonyl,arylsulphonylamino, alkylsulphonylamino, hydroxy,morpholinylalkylaminocarbonyl, hydroxyaminocarbonyl, aryloxy,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylalkylthio andhalogen.

[0049] Alkenyl and alkynyl groups referred to herein include straightand branched chain groups containing from two to twelve, suitably fromtwo to six, carbon atoms. These alkenyl and alkynyl groups may beoptionally substituted with up to five, suitably up to three, groupsincluding those substituents described hereinbefore for the alkylgroups.

[0050] As used herein the term “carbocyclic” includes aromaticcarbocyclic rings, for example aryl groups, and non-aromatic carbocyclicgroups, for example cycloalkyl and cycloalkenyl groups, and fusedcarbocyclic ring systems wherein the carbocyclic rings may be aromaticor non-aromatic, for example indanyl.

[0051] Cycloalkyl and cycloalkenyl groups referred to herein includegroups having between three and eight ring carbon atoms. Thesecycloalkyl and cycloalkenyl groups may be optionally substituted with upto five, suitably up to three, groups including those substituentshereinbefore described for the alkyl groups.

[0052] As used herein, the term “aryl” includes phenyl, naphthyl, andbiphenyl groups, especially phenyl. Suitable optional substituents forany aryl group include up to five substituents selected from the listconsisting of perhaloalkyl, arylaminocarbonyl, aralkyaminocarbonyl,hydroxyalkylaminocarbonyl, arylamino, aminosulphonyl,alkylsulphonylamino, mono- and di-alkylamino, mono- anddi-alkylaminocarbonyl, arylaminocarbonylalkyl, arylcarbonyl, aralkoxy,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylalkylthio,arylcarbonylamino, alkoxyalkylaminocarbonyl, aralkylcarbonylamino,aralkylcarbonylaminoalkyl, aminocarbonyl,morpholinylalkylaminocarbonylalkyl, arylaminosulphonyl,arylcarbonylaminoalkyl, arylsulphonylamino, aminocarbonylalkyl,hydroxyaminocarbonylalkyl, aryl, alkylcarbonylamino, alkylenedioxy,perhaloalkoxy, thiazolidinedionylalkyl, carboxyalkoxy,(methylpiperazinyl)carbonylalkyl, morpholinyl, morpholinylcarbonylalkyl,piperidinylcarbonylalkyl, hydroxyalkylaminocarbonylalkyl, mono- anddi-alkylaminocarbonylalkyl, alkoxyalkylaminosulphonyl, alkoxyamino,perhaloalkylcarbonylamino, alkylaminosulphonylalkyl, mono- and di-alkylaminoalkylaminocarbonylalkyl, carboxyalkoxy,alkoxycarbonylaminoalkyl, aminocarbonylalkenyl,alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino,alkylcarbonylaminoalkyl, hydroxyalkylcarbonylamino,alkoxycarbonylalkylcarbonylamino, carboxyalkylcarbonylamino,alkoxyalkylcarbonylaminoalkyl, alkylcarbonylaminoalkylcarbonylamino,hydroxyalkylcarbonylaminoalkyl, carboxyalkenyl,aminocarbonylalkylcarbonylamino, alkylaminocarbonylalkoxy,alkylaminosulphonylalkyl, aminocarbonylalkyl, oxazolyl,pyridinylalkylcarbonylamino, methyloxazolyl, alkylthio,alkylaminocarbonylalkyl, halo, alkyl, alkenyl, substituted alkenyl,arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkyloxy, hydroxy,hydroxyalkyl, nitro, amino, cyano, cyanoalkyl, mono- anddi-N-alkylamino, acyl, acylamino, N-alkylacylamino, acyloxy, carboxy,carboxyalkyl, carboxyalkylcarbonyl, carboxyalkenyl, ketoalkylester,carbamoyl, carbamoylalkyl, mono- and di-N-alkylcarbamoyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxy, arylthio, aralkyloxy,aryloxycarbonyl, ureido, guanidino, morpholino, adamantyl, oxazolyl,aminosulphonyl, alkylaminosulphonyl, alkylthio, haloalkylthio,alkylsulphinyl, alkylsulphonyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, alkoxycarbonyl, trityl, substituted trityl, mono- orbis-alkylphosphonate or mono- or bis-alkylphosphonateC₁₋₆alkyl or anytwo adjacent substituents on the phenyl ring together with the carbonatoms to which they are attached form a carbocyclic ring or aheterocyclic ring.

[0053] As used herein the terms “heterocyclyl” and “heterocyclic”suitably include, unless otherwise defined, aromatic and non-aromatic,single and fused, rings suitably containing up to four heteroatoms ineach ring, each of which is selected from oxygen, nitrogen and sulphur.Each ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. Theseheterocyclyl and heterocyclic rings may be unsubstituted or substitutedby up to five substituents. A fused heterocyclic ring system may includecarbocyclic rings and need include only one heterocyclic ring. Examplesinclude furyl, piperazinyl, thienyl, piperidinyl, pyridazinyl,morpholinyl, pyridyl, indolinyl, quinolinyl, indolyl, benzoxazolyl,benzothiazolyl, benzothiazolinonyl, and benzoxazolinonyl. Suitablesubstituents for any heterocyclyl or heterocyclic group are selectedfrom cyano, carboxyalkoxy, morpholinyl, hydroxyalkylaminocarbonyl,alkoxyalkylaminosulphonyl, alkylaminosulphonyl, arylcarbonylamino,aralkylcarbonylamino, aralkenylcarbonylamino, perhalocarbonylanmino,perhaloalkyl, aminocarbonyl, nitro, aminocarbonylalkenyl,alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino,hydroxyalkylcarbonylamino, carboxyalkenyl,aminocarbonylalkylcarbonylanino, alkylaminocarbonylalkoxy, aryl,arylcarbonyl, alkylenedioxy, aryloxy, aralkyloxy, perhaloalkylthio,alkcylcarbonyl, alkoxycarbonylalkylthio, carboxyalkylthio, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonyl, halogen, alkyl,arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxy, amino, mono- anddi-N-alkylamino, acylamino, carboxy and salts and esters thereof,carbamoyl, mono- and di-N-alkylaminocarbonyl, aryloxycarbonyl,alkoxycarbonylalkyl, aryl, oxy groups, ureido, guanidino,sulphonylamino, aminosulphonyl, alkylthio, alkylsulphinyl,alkylsulphonyl, cyano, hydroxy, alkylcarbonylamino, heterocyclyl andheterocyclylalkyl.

[0054] As used herein the term “heteroaryl” suitably includes, unlessotherwise defined, aromatic single and fused rings suitably containingup to four heteroatoms in each ring, each of which is selected fromoxygen, nitrogen and sulphur. Each ring suitably has from 4 to 7,preferably 5 or 6, ring atoms. These heteroaryl rings may beunsubstituted or substituted by up to five substituents. A fusedheteroaryl ring system may include carbocyclic rings and need includeonly one heteroaryl ring. Examples include furyl, thienyl, pyridazinyl,pyridyl, quinolinyl, indolyl, benzoxazolyl, and benzothiazolyl. Suitablesubstituents for any heteroaryl group are selected from cyano,carboxyalkoxy, morpholinyl, hydroxyalkylaminocarbonyl,alkoxyalkylaminosulphonyl, alkylaminosulphonyl, arylcarbonylamino,aralkylcarbonylamino, aralkenylcarbonylamino, perhalocarbonylamino,perhaloalkyl, aminocarbonyl, nitro, aminocarbonylalkenyl,alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino,hydroxyalkylcarbonylamino, carboxyalkenyl,aminocarbonylalkylcarbonylamino, alkylaminocarbonylalkoxy, aryl,arylcarbonyl, alkylenedioxy, aryloxy, aralkyloxy, perhaloalkylthio,alkylcarbonyl, alkoxycarbonylalkylthio, carboxyalkylthio, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonyl, halogen, alkyl,arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxy, amino, mono- anddi-N-alkylamino, acylamino, carboxy and salts and esters thereof,carbamoyl, mono- and di-N-alkylaminocarbonyl, aryloxycarbonyl,alkoxycarbonylalkyl, aryl, oxy groups, ureido, guanidino,sulphonylamino, aminosulphonyl, alkylthio, alkylsulphinyl,alkylsulphonyl, cyano, hydroxy, alkylcarbonylamino, heterocyclyl andheterocyclylalkyl.

[0055] As used herein the terms “halogen” or “halo” include iodo, bromo,chloro or fluoro, especially chloro or fluoro.

[0056] Suitable derivatives of the compounds of the invention arepharmaceutically acceptable derivatives.

[0057] Suitable derivatives of the compounds of the invention includesalts and solvates.

[0058] Suitable pharmaceutically acceptable derivatives includepharmaceutically acceptable salts and pharmaceutically acceptablesolvates.

[0059] Suitable pharmaceutically acceptable salts include metal salts,such as for example aluminium, alkali metal salts such as lithium,sodium or potassium, alkaline earth metal salts such as calcium ormagnesium and ammonium or substituted ammonium salts, for example thosewith lower alkylamines such as triethylamine, hydroxy alkylamines suchas 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

[0060] Suitable pharmaceutically acceptable salts also includespharmaceutically acceptable acid addition salts, such as those providedby pharmaceutically acceptable inorganic acids or organic acids.

[0061] Suitable pharmaceutically acceptable acid addition salts providedby pharmaceutically acceptable inorganic acids includes the sulphate,nitrate, phosphate, borate, hydrochloride and hydrobromide andhydroiodide.

[0062] Suitable pharmaceutically acceptable acid addition salts providedby pharmaceutically acceptable organic acids includes the acetate,tartrate, maleate, fumarate, malonate, citrate, succinate, lactate,toluene sulphonate, trifluoroacetate, oxalate, benzoate, ascorbate,methanesulphonate, α-keto glutarate and α-glyerophosphate.

[0063] Suitable pharmaceutically acceptable solvates include hydrates.

[0064] For the avoidance of doubt when used herein the term “diabetes”includes diabetes mellitus, especially Type 2 diabetes, and conditionsassociated with diabetes mellitus.

[0065] The term “conditions associated with diabetes” includes thoseconditions associated with the pre-diabetic state, conditions associatedwith diabetes mellitus itself and complications associated with diabetesmellitus.

[0066] The term “conditions associated with the pre-diabetic state”includes conditions such as insulin resistance, impaired glucosetolerance and hyperinsulinaemia.

[0067] The term “conditions associated with diabetes mellitus itself”include hyperglycaemia, insulin resistance and obesity. Furtherconditions associated with diabetes mellitus itself include hypertensionand cardiovascular disease, especially atherosclerosis and conditionsassociated with insulin resistance. Conditions associated with insulinresistance include polycystic ovarian syndrome and steroid inducedinsulin resistance.

[0068] The term “complications associated with diabetes mellitus”includes renal disease, especially renal disease associated with Type IIdiabetes, neuropathy and retinopathy. Renal diseases associated withType II diabetes include nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis and endstage renal disease.

[0069] A further aspect of the invention provides a process for thepreparation of a compound of formula (I), or a derivative thereof, whichprocess comprises reaction of a compound of formula (II),

[0070] wherein;

[0071] R² is as defined in formula (I), with a compound of formula(III),

[0072] wherein;

[0073] R¹ is as defined in formula (I) and X is a leaving group, andthereafter, if required, carrying out one or more of the followingoptional steps:

[0074] (i) converting a compound of formula (I) to a further compound offormula (I);

[0075] (ii) removing any necessary protecting group;

[0076] (iii) preparing an appropriate derivative of the compound soformed.

[0077] Examples of suitable leaving groups, X, are chloro and acyloxy.

[0078] The reaction between the compounds of formulae (II) and (III) iscarried out in a suitable solvent under conventional amidationconditions a suitable temperature providing a suitable rate of formationof the required product, generally an elevated temperature, over asuitable reaction time. Suitable solvents include pyridine. Suitablereaction temperatures include those in the range of 60° C. to 220° C.and, as appropriate, the reflux temperature of the solvent. Suitablereaction times are those in the range 12-96 hours. If the compound offormula (II) is a weak nucleophile, then the reaction may be assistedby, for example, using temperatures at the upper end of this range, orby using a hindered base catalyst such as dimethylaminopyridine (DMAP).A hindered base is a base which does not act as a competing nucleophile.The reaction products are isolated using conventional methods.Typically, the reaction mixture is cooled, the residue concentrated andthe product purified by conventional methods such as crystallisation,chromatography, purification by ion-exchange filtration or trituration.Suitable methods of chromatography include, for example, silica gelchromatography, and reverse-phase preparative HPLC. Suitableion-exchange resins include acid ion-exchange resins, for example, SCXresin. It will be appreciated that the purification of a compound offormula (I) may require more than one chromatography step and mayadditionally require purification with a suitable ion-exchange resin.Conventional methods of heating and cooling may be employed, forexample, thermostatically controlled oil baths and ice/salt bathsrespectively. Crystalline product may be obtained by standard methods.

[0079] Compounds of formula (II) are believed to be novel andaccordingly form a further aspect of the invention.

[0080] In the reaction of a compound of formula (II) with a compound offormula (III), a compound of formula (V) may be formed,

[0081] wherein;

[0082] R¹ and R² are as hereinbefore defined.

[0083] A compound of formula (V) may be converted into a compound offormula (I) either in situ or in a separate step, by reaction with asuitable nucleophile, such as piperidine or a polyamine resin.

[0084] Thus, according to the present invention there is provided aprocess for the preparation of a compound of formula (I) or a derivativethereof, which process comprises reaction of a compound of formula (V),as defined hereinbefore, with a nucleophile, and thereafter, ifrequired, carrying out one or more of the following optional steps:

[0085] (i) converting a compound of formula (I) to a further compound offormula (I);

[0086] (ii) removing any necessary protecting group;

[0087] (iii) preparing an appropriate derivative of the compound soformed.

[0088] Compounds of formula (V) are considered to be novel andaccordingly form a further aspect of the invention.

[0089] In a preferred aspect, the compound of formula (III) is added toa solution of the compound of formula (II) in pyridine. The reactionmixture is stirred at reflux for 17 hours, allowed to cool, andconcentrated. The crude product is purified by chromatography, forexample, silica gel chromatography.

[0090] The above mentioned conversion of a compound of formula (I) intoanother compound of formula (I) includes any conversion which may beeffected using conventional procedures, but in particular the saidconversions include any combination of:

[0091] (i) converting one group R¹ into another group R¹;

[0092] (ii) converting one group R² into another group R².

[0093] The above mentioned conversions (i) and (ii) may be carried outusing any appropriate method under conditions determined by theparticular groups chosen.

[0094] The above mentioned conversions may as appropriate be carried outon any of the intermediate compounds mentioned herein.

[0095] Suitable protecting groups in any of the above mentionedreactions are those used conventionally in the art. The methods offormation and removal of such protecting groups are those conventionalmethods appropriate to the molecule being protected. Thus for example abenzyloxy group may be prepared by treatment of the appropriate compoundwith a benzyl halide, such as benzyl bromide, and thereafter, ifrequired, the benzyl group may be conveniently removed using catalytichydrogenation or a mild ether cleavage reagent such as trimethylsilyliodide or boron tribromide Where appropriate individual isomeric formsof the compounds of formula (I) may be prepared as individual isomersusing conventional procedures.

[0096] The absolute stereochemistry of compounds may be determined usingconventional methods, such as X-ray crystallography.

[0097] The derivatives of the compounds of formula (I), including saltsand/or solvates, may be prepared and isolated according to conventionalprocedures.

[0098] Compounds of formula (II) may be prepared by reaction of acompound of formula (IV)

[0099] wherein;

[0100] R² is as defined in formula (I), with hydrazine, or a hydratethereof.

[0101] The reaction between the compound of formula (I) and hydrazine,or a hydrate thereof, is carried out in a suitable solvent at a suitabletemperature providing a suitable rate of formation of the requiredproduct, generally an elevated temperature, over a suitable reactiontime. Suitable solvents include pyridine. Suitable reaction temperaturesinclude those in the range of 60° C. to 220° C. and, as appropriate, thereflux temperature of the solvent. Suitable reaction times are those inthe range 1-8 hours. The reaction products are isolated usingconventional methods. Typically, the reaction mixture is cooled, theproduct isolated by filtration, and dried. Conventional methods ofheating and cooling may be employed, for example electric heatingmantles and ice/salt baths respectively. The reaction products may, ifdesired, be purified by conventional methods, such as crystallisation,chromatography and trituration.

[0102] In a preferred aspect, hydrazine hydrate is added to a stirredsolution of the compound of formula (I) in pyridine. The reactionmixture is stirred at reflux for 3 hours and cooled. The crude productis purified by chromatography.

[0103] Compounds of formula (IV) may be prepared from2,5-dichloro-isonicotinonitrile (WO 96/33975) employing conventionalcross-coupling procedures disclosed in standard reference texts ofsynthetic methodology such as March's Advanced Organic Chemistry:Reactions Mechanisms, and Structures, 5th Edition, Wiley, 2001.

[0104] Compounds of formula (III) are either commercially available, orare prepared by analogy with known conventional literature procedures,for example those disclosed in standard reference texts of syntheticmethodology such as March's Advanced Organic Chemistry: Reactions,Mechanisms, and Structures, 5th Edition, Wiley, 2001.

[0105] As stated above, the compounds of formula (I), orpharmaceutically acceptable derivatives thereof, are indicated to beuseful as inhibitors of GSK-3.

[0106] The invention therefore provides a compound of formula (I), or apharmaceutically acceptable derivative thereof, for use as an inhibitorof GSK-3.

[0107] Accordingly, the present invention also provides a method for thetreatment of conditions associated with a need for inhibition of GSK-3such as diabetes, conditions associated with diabetes, chronicneurodegenerative conditions including dementias such as Alzheimer'sdisease, Parkinson's disease, progressive supranuclear palsy, subacutesclerosing panencephalitic parkinsonism, postencephalitic parkinsonism,pugilistic encephalitis, guam parkinsonism-dementia complex, Pick'sdisease, corticobasal degeneration, frontotemporal dementia,Huntingdon's disease, AIDS associated dementia, amyotrophic lateralsclerosis, multiple sclerosis and neurotraumatic diseases such as acutestroke, mood disorders such as schizophrenia and bipolar disorders,promotion of functional recovery post stroke, cerebral bleeding (forexample, due to solitary cerebral amyloid angiopathy), hair loss,obesity, atherosclerotic cardiovascular disease, hypertension,polycystic ovary syndrome, syndrome X, ischaemia, traumatic braininjury, cancer, leukopenia, Down's syndrome, Lewy body disease,inflammation, and immunodeficiency, which method comprises theadministration of a pharmaceutically effective, non-toxic amount of acompound of formula (I) or a pharmaceutically acceptable derivativethereof,

[0108] The present invention further provides a compound of formula (I),or a pharmaceutically acceptable derivative thereof, for use as aninhibitor of glycogen synthase kinase-3, and especially for use in thetreatment of conditions associated with a need for the inhibition ofGSK-3, such as diabetes, conditions associated with diabetes, chronicneurodegenerative conditions including dementias such as Alzheimer'sdisease, Parkinson's disease, progressive supranuclear palsy, subacutesclerosing panencephalitic parkinsonism, postencephalitic parkinsonism,pugilistic encephalitis, guam parkinsonism-dementia complex, Pick'sdisease, corticobasal degeneration, frontotemporal dementia,Huntingdon's disease, AIDS associated dementia, amyotrophic lateralsclerosis, multiple sclerosis and neurotraumatic diseases such as acutestroke, mood disorders such as schizophrenia and bipolar disorders,promotion of functional recovery post stroke, cerebral bleeding (forexample, due to solitary cerebral amyloid angiopathy), hair loss,obesity, atherosclerotic cardiovascular disease, hypertension,polycystic ovary syndrome, syndrome X, ischaemia, traumatic braininjury, cancer, leukopenia, Down's syndrome, Lewy body disease,inflammation, and immunodeficiency.

[0109] The present invention also provides the use of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, forthe manufacture of a medicament for the treatment of conditionsassociated with a need for the inhibition of GSK-3, such as diabetes,conditions associated with diabetes, chronic neurodegenerativeconditions including dementias such as Alzheimer's disease, Parkinson'sdisease, progressive supranuclear palsy, subacute sclerosingpanencephalitic parkinsonism, postencephalitic parkinsonism, pugilisticencephalitis, guam parkinsonism-dementia complex, Pick's disease,corticobasal degeneration, frontotemporal dementia, Huntingdon'sdisease, AIDS associated dementia, amyotrophic lateral sclerosis,multiple sclerosis and neurotraumatic diseases such as acute stroke,mood disorders such as schizophrenia and bipolar disorders, promotion offunctional recovery post stroke, cerebral bleeding (for example, due tosolitary cerebral amyloid angiopathy), hair loss, obesity,atherosclerotic cardiovascular disease, hypertension, polycystic ovarysyndrome, syndrome X, ischaemia, traumatic brain injury, cancer,leukopenia, Down's syndrome, Lewy body disease, inflammation, andimmunodeficiency.

[0110] In a further aspect of this invention, there is provided acompound of formula (I), or a pharmaceutically acceptable derivativethereof, for use as an active therapeutic substance.

[0111] Preferably, the compounds of formula (I), or pharmaceuticallyacceptable derivatives thereof, are administered as pharmaceuticallyacceptable compositions.

[0112] Accordingly, the invention also provides a pharmaceuticalcomposition which comprises a compound of formula (I), or apharmaceutically acceptable derivative thereof, and a pharmaceuticallyacceptable carrier.

[0113] The active compounds are usually administered as the solemedicament agent but they may be administered in combination with othermedicament agents as dictated by the severity and type of disease beingtreated. For example in the treatment of diabetes, especially Type 2diabetes, a compound of formula (I), or a pharmaceutically acceptablederivative thereof, may be used in combination with other medicamentagents, especially antidiabetic agents such as insulin secretagogues,especially sulphonylureas, insulin sensitisers, especially glitazoneinsulin sensitisers (for example thiazolidinediones), or with biguanidesor alpha glucosidase inhibitors or the compound of formula (I), or apharmaceutically acceptable derivative thereof, may be administered incombination with insulin.

[0114] The said combination comprises co-administration of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, and anadditional medicament agent or the sequential administration of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, and the additional medicament agent.

[0115] Co-administration includes administration of a pharmaceuticalcomposition which contains both a compound of formula (I), or apharmaceutically acceptable derivative thereof, and the additionalmedicament agent or the essentially simultaneous administration ofseparate pharmaceutical compositions of a compound of formula (I), or apharmaceutically acceptable derivative thereof, and the additionalmedicament agent.

[0116] The compositions of the invention are preferably adapted for oraladministration. However, they may be adapted for other modes ofadministration. The compositions may be in the form of tablets,capsules, powders, granules, lozenges, suppositories, reconstitutablepowders, or liquid preparations, such as oral or sterile parenteralsolutions or suspensions. In order to obtain consistency ofadministration it is preferred that a composition of the invention is inthe form of a unit dose. Preferably the compositions are in unit dosageform. A unit dose will generally contain from 0.1 to 1000 mg of theactive compound.

[0117] Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 800 mg/kg/day.

[0118] Suitable dose forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

[0119] The solid oral compositions may be prepared by conventionalmethods of blending, filling or tabletting. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

[0120] Oral liquid preparations may be in the form of, for example,emulsions, syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

[0121] For parenteral administration, fluid unit dosage forms areprepared utilizing the compound and a sterile vehicle, and, depending onthe concentration used, can be either suspended or dissolved in thevehicle. In preparing solutions the compound can be dissolved in waterfor injection and filter sterilized before filling into a suitable vialor ampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

[0122] The formulations mentioned herein are carried out using standardmethods such as those described or referred to in reference texts suchas the British and US Pharmacopoeias, Remington's PharmaceuticalSciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia(London, The Pharmaceutical Press) or the above mentioned publications.

[0123] Suitable methods for preparing and suitable unit dosages for theadditional medicament agent, such as the antidiabetic agent mentionedherein include those methods and dosages described or referred to in theabove mentioned reference texts.

GSK-3 Assay

[0124] GSK-3 assays used to test the compounds of the invention includethe following protocol which is based on the ability of the kinase tophosphorylate a biotinylated 27 mer peptide, Biot-KYRRAAVPPSPSLSRHSSPHQ(S)EDEEE, the sequence of which is derived from thephosphorylation site of glycogen synthase, where (S) is apre-phosphorylated serine as in glycogen synthase in vivo and the threeconsensus sites for GSK-3 specific phosphorylation are underlined. Thephosphorylated biotinylated peptide is then captured onto Streptavidincoated SPA beads (Amersham Technology), where the signal from the ³³P isamplified via the scintillant contained in the beads.

[0125] Using microtitre plates, GSK-3 was assayed in 50 mM MOPS buffer,pH 7.0, containing 5% glycerol, 0.01% Tween-20, 7.5 mM2-mercaptoethanol, 10 mM magnesium acetate, 8 uM of the above peptide,and 10 uM [³³P]-ATP. After incubation at room temperature, the reactionwas stopped by addition of 50 mM EDTA solution containing theStreptavidin coated SPA beads to give a final 0.2 mgs. Followingcentrifugation, the microtitre plates are counted in a Trilux 1450microbeta liquid scintillation counter (Wallac). IC₅₀ values aregenerated for each compound by fitting to a four parameter model.

[0126] The most potent compounds of the present invention show IC₅₀values in the range of 1 to 500 nM.

[0127] No adverse toxicological effects are expected for the compoundsof the invention, when administered in accordance with the invention.

[0128] The following Descriptions and Examples illustrate the invention,but do not limit it in any way.

SYNTHETIC METHOD A EXAMPLE 1N-(5-Phenyl-1H-pyrazolo[3,4c]pyridin-3-yl)butyramide

[0129] n-Butyric anhydride (70 uL, 0.43 mmol) was added to a solution of5-phenyl-1H-pyrazolo[3,4-c]pyridin-3-ylamine (90 mg, 0.43 mmol) inpyridine (0.5 mL). The reaction mixture was stirred at reflux for 17hours, allowed to cool and concentrated. Purification by columnchromatography using 4% v/v methanol in chloroform as eluent affordedthe title compound as a solid.

[0130] MS (APCI+ve): [M+H]⁺ at m/z 281 (C₁₆H₁₆N₄O) requires [M+H]⁺ atm/z 281. ¹H NMR δ (DMSO-d₆) 13.4 (1H, br), 10.8 (1H, s), 9.1 (1H, s),8.3 (1H, s), 8.0 (2H, d), 7.6-7.4 (3H, m), 2.4 (2H, t), 1.6 (2H, q), 1.0(3H, t).

[0131] The starting material for Example 1 may be prepared according toDescriptions 1 & 2 below.

Description 1 5-Chloro-2-phenyl-isonicotinonitrile

[0132] Tetralds(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol) wasadded to a stirred solution of phenylboronic acid (423 mg, 3.47 mmol),2,5-dichloro-isonicotinonitrile (550 mg, 2.89 mmol) and sodium carbonate(3.5 mL of 2M aqueous solution) in dimethoxyethane (7 mL) and ethanol(3.5 mL). The resulting suspension was stirred at reflux for 3 hours,concentrated in vacuo and water (25 mL) added. The aqueous solution wasextracted with ethyl acetate (×3) and the combined organic extracts werewashed with brine, dried and concentrated. Purification by columnchromatography using 2% v/v ethyl acetate in hexane as eluent affordedthe title compound as a solid.

[0133] MS (APCI+ve): [M+H]⁺ at m/z 215 (C₁₂H₇C1N₂) requires [M+H]⁺ atm/z 215. ¹H NMR δ (CDCl₃) 8.8 (1H, s), 8.1-7.9 (3H, m), 7.6-7.4 (3H, m).

Description 2 5-Phenyl-1H-pyrazolo[3,4-c]pyridin-3-ylamine

[0134] Hydrazine hydrate (0.3 mL, 5.9 mmol) was added to a stirredsolution of 5-chloro-2-phenyl-isonicotinonitrile (420 mg, 1.9 mmol) inpyridine (5 mL). The reaction mixture was stirred at reflux for 3 hours,cooled and the resulting solid was filtered and dried in vacuo,affording a crude residue. Purification by column chromatography using agradient elution of 0-5% methanol in dichloromethane as eluent affordedthe title compound as a solid. ¹H NMR δ (DMSO-d₆) 11.9 (1H, s) 8.8 (1H,s), 8.3 (1H, s), 8.0 (2H, d), 7.5 (2H, appt), 7.3 (1H, appt), 5.6 (2H,s).

SYNTHETIC METHOD B EXAMPLE 2N-[5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl]isobutyramide

[0135] 5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine(Description 3; 100 mg, 0.41 mmol) was reacted with isobutyryl chloride(43 uL, 0.41 mmol) in pyridine (0.5 mL) in a manner analogous to thatdescribed in Example 1. Chromatography on silica gel using 4% v/vmethanol in dichloromethane as eluent afforded the title compound as asolid.

[0136] MS (APCI+ve): [M+H]⁺ at m/z 317 (C16H₁₄F₂N₄O) requires [M+H]⁺ atm/z 317). 1H NMR δ(DMSO-d₆) 13.35 (1H, br s), 10.6 (1H, s), 9.1 (1H, s),8.3 (1H, s), 7.8 (1H, m), 7.45 (1H, m), 7.3 (1H, m), 2.8 (1H, m) and1.15 (6H,d).

[0137] The starting material for Example 2 may be prepared according toDescription 3 below.

Description 3 5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine

[0138] Hydrazine hydrate (0.52 ml, 10.7 mmol) was added to a stirredsolution of 5-chloro-2-(2,3-difluorophenyl)isonicotinonitrile (1.22 g,4.9 mmol) in pyridine (12.5 mL). The reaction mixture was stirred atreflux for 2 hours, allowed to cool and concentrated. Purification bycolumn chromatography using a gradient of 5-10% methanol indichloromethane as eluent afforded the title compound as a solid.

[0139] MS (APCI+ve): [M+H]⁺ at m/z 247 (C₁₂H₈F₂N₄ requires [M+H]⁺ at m/z247). 1H NMR δ (DMSO-d₆) 12.1 (1H, s), 8.85 (1H, s), 8.2 (1H, s), 7.8(1H, t), 7.4 (1H, m), 7.3 (1H, m), 5.7 (2H, s).

SYNTHETIC METHOD C EXAMPLE 4 1-Methyl4-piperidinecarboxylic acid[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl]amidehydrochloride

[0140] 1-Methyl4-piperidinecarbonyl chloride hydrochloride (400 mg, 2.02mmol) was added to a solution of5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (100 mg, 0.41mmol) in pyridine (4.5 mL). The reaction mixture was stirred at refluxfor 48 hours, allowed to cool and concentrated. Purification by columnchromatography using 20% v/v of a 2M methanolic ammonia solution inchloroform as eluent, and subsequent treatment of the product with 1Mhydrogen chloride in ether afforded the title compound as a solid.

[0141] MS (APCI+ve): [M+H]⁺ at m/z 372 (C₁₉H₁₉F₂N₅O requires [M+H]⁺ atm/z 372). 1H NMR δ (DMSO-d₆) 13.5 (1H, br s), 10.9 (1H, s), 10.25 (1H,br s), 9.1 (1H, s), 8.3 (1H, s), 7.8 (1H, t), 7.45 (1H, q), 7.3 (1H, m),3.5 (2H, d), 3.0 (2H, q), 2.75 (3H, s), 2.1 (2H, m) and 1.95 (2H, m).

SYNTHETIC METHOD D EXAMPLE 15 Cyclopropanecarboxylic acid[5-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]amide

[0142] Cyclopropanecarboxylic acid[1-(1-cyclopropylmethanoyl)-5-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]amide(Description 4; 196 mg, 0.542 mmol), was dissolved in piperidine (2 mL)and stirred at room temperature for 16 hours. The piperidine was removedin vacuo, and the resulting oily residue was triturated with water togive the title compound as a solid.

[0143] MS (APCI+ve): [M+H]⁺ at m/z 294 (C₁₆H₁₅N₅O requires [M+H]⁺ at m/z294). ¹H NMR δ (DMSO-d₆): 0.91 (4H, m), 1.91 (1H, br m), 3.30 (3H,singlet obscured by water signal), 7.34 (1H, d), 8.22 (1H, d), 8.32 (1H,s), 9.05 (2H d,). NH protons presumed exchanged with solvent.

[0144] The starting material for Example 15 may be prepared according toDescription 4 below.

Description 4 Cyclopropanecarboxylic acid[1-(1-cyclopropylmethanoyl)-5-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]amide

[0145] Cyclopropanecarbonyl chloride (186 mg, 1.776 mmol) was added to astirred solution of5-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (200 mg,0.888 mmol) in anhydrous pyridine (5 mL) and the reaction was heatedunder reflux for 16 hours. The solvent was removed in vacuo, and theresidue chromatographed on silica gel using 10% v/v methanol indichloromethane as eluent to afford the title compound as a solid.

[0146] MS (APCI+ve): [M+H]⁺ at m/z 362 (C₂₀H₁₉N₅O₂ requires [+H]⁺ at m/z362). ¹H NMR δ (DMSO-₆): 0.94 (4H, m), 1.21 (4H, m), 2.09 (1H, br m),2.54 (3H, s), 3.02 (1H, m), 7.40 (1H, d), 8.29 (1H, d), 8.55 (1H, s),9.11 (1H, s), 9.66 (1H, s), 11.35 (1H, br s).

SYNTHETIC METHOD E EXAMPLE 20N-(5-Phenyl-1H-pyrazolo[3,4-c]pyridin-3-yl)4-(piperidin-1-yl)butyramidebitartrate Salt

[0147] 3-Amino-5-phenyl-1H-pyrazolo[3,4-c]pyridine (0.2 g, 0.951 mmol)was added to the hydrochloride salt of 4-(piperidin-1-yl)butyric acidchloride (0.861 g, 3.81 mmol) in dry pyridine (10 mL) and the mixtureheated at reflux under argon for 24 hours. After being allowed to cool,the resulting solid (a bis-amide) was collected and dried. The bis-amidewas dissolved in dichloromethane (18 mL) and shaken with polyamine resin(1.107 g, 3.2 mmol/g, 4 equiv.) for 72 hours. After filtration, theresin was washed sequentially with dichloromethane (3×10 mL) followed by10% v/v methanol in dichloromethane (3×10 mL) and solvents evaporated toafford the crude product, which was purified firstly by preparative HPLCusing a gradient elution of 10-90% acetonitrile (containing 0.01%trifluoroacetic acid) in water (containing 0.1% trifluoroacetic acid),followed by passage of the product fractions through an SCX column.Product was retained on the column during washing with methanol (20 mL)and then eluted with 0.5N ammonia in methanol (20 mL) to afford thetitle compound as the free base.

[0148] A solution of this free base in methanol (3 mL) was mixed with anequivalent of tartaric acid in methanol (3 mL) and then evaporated todryness. The residue was triturated with acetone then dried under highvacuum to afford the title compound as a solid.

[0149] MS (AP+ve): [M+H]⁺ at m/z 364 (C₂₁H₂₅N₅O requires [M+H]⁺ at m/z364) ¹H NMR δ (DMSO-d₆): 1.48 (2H, m), 1.64 (4H, m), 1.94 (2H, m),2.45-2.60 (2H, m overlapped by DMSO signal), 2.70-3.95 (6H, m, partlyoverlapped by water signal), 4.02 (2H, s), 7.37 (1H, t), 7.49 (2H, t),8.02 (2H, d), 8.32 (1H, d), 9.03 (1H, d), 10.74 (1H, br s) and 13.25(1H, br s). The remaining acidic protons and the hydroxyl protons of thebitartrate were not observed and these are presumed exchanged with thewater signal.

SYNTHETIC METHOD F EXAMPLE 20 Cyclopropanecarboxylic acidN-[5-(quinolin-3-yl)-1H-pyrazolo[3,4]pyridin-3-yl]amide

[0150] Cyclopropane carbonyl chloride (168 mg, 1.602 mmol) was added toa stirred solution of5-(quinolin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (200 mg, 0.766mmol) in anhydrous pyridine (5 mL) and the reaction was heated underreflux for 16 hours. The solvent was then removed in vacuo and theresidue re-evaporated from water (10 mL) to yield a solid. This wastriturated with saturated aqueous sodium bicarbonate solution and themixture then left to stand for 0.5 hour until the pH stabilised at pH9-10. The resulting solid was then collected by filtration, washed withwater (3×25 mL) and dried in vacuo. This material was then stirred inpiperidine (3 mL) at room temperature for 2 hours. The piperidine wasevaporated and the residue triturated with water (5 mL) and withmethanol (5 mL) to afford the title compound as a solid.

[0151] MS (APCI+ve): [M+H]⁺ at m/z 330 (C₁₉H₁₅N₅O requires [M+H]⁺ at m/z330). ¹HNMR δ (DMSO-d₆): 0.88 (2H, m), 0.95 (2H, s), 1.99 (1H, br m),7.65 (1H, t), 7.78 (1H, t), 8.06 (1H, d), 8.13 (1H, d), 8.53 (1H, s),8.90 (1H, s), 9.12 (1H, s), 9.59 (1H, s), 11.0 (1H, br s) and 13.35 (1H,br s).

[0152] Further Examples of the invention are illustrated in Table 1. Thefurther examples described herein were prepared by analogy withSynthetic Methods A-F disclosed above. TABLE 1 (I)

LC/MS [M + H]⁺ Observed Calculated (Unless [M]^(- or) Example SyntheticMolecular [M-H]- are No Method R¹ R² Weight (M) indicated) 1 A n-Pr Ph280.329 281 2 B i-Pr 2,3-di-F-Ph 316.31 317 3 B cyc-Pentyl 2,3-di-F-Ph342.347 343 4 C N-Me-Pipieridin-4-yl 2,3-di-F-Ph 371.389 372 5 B cyc-PrPh 278.314 279 6 B i-Pr Ph 280.329 281 7 B i-Pr 2-Cl-Ph 314.775 315/3178 B cyc-Pentyl 2-Cl-Ph 340.812 341/343 9 C (CH2)3(Piperidin-1-yl)2-Cl-Ph 397.908 398/400 10 B cyc-Pr Pyridin-3-yl 279.302 280 11 B i-PrPyridin-3-yl 281.318 282 12 C (CH2)3(4-Et-Piperazin-1-yl) Pyridin-3-yl393.492 394 13 C (CH2)3(4-Et-Piperazin-1-yl) 2-Cl-Ph 426.949 427/429 14C (CH2)3(Pyrrolidin-1-yl) 2-Cl-Ph 383.881 384/386 15 D cyc-Pr6-Me-Pyridin-3-yl 293.328 294 16 D cyc-Pr 2-Cl-Ph 312.759 313/315 17 C(CH2)3(Pyrrolidin-1-yl) Pyridin-3-yl 350.424 351 18 C (CH2)3NMe2 2-Cl-Ph357.843 358/360 19 C (CH2)3(Pyrrolidin-1-yl) Ph 349.436 350 20 E(CH2)3(Piperidin-1-yl) Ph 363.462 364 21 C (CH2)3(4-Et-Piperazin-1-yl)Ph 392.504 393 22 B cyc-Pr 2,3-di-F-Ph 314.294 315 23 F cyc-PrQuinolin-3-yl 329.362 330 24 B cyc-Pr 6-OMe-Pyridin-3-yl 309.327 310 25D i-Pr 5-Ph-Pyridin-3-yl 357.415 358 26 C N-Me-Piperidin-4-yl6-Me-Pyridin-3-yl 350.424 351 27 C (CH2)3(4-Et-Piperazin-1-yl)6-Me-Pyridin-3-yl 407.519 408 28 C (CH2)3(4-Et-Piperazin-1-yl)2,3-di-F-Ph 428.484 429 29 C (CH2)3(Pyrrolidin-1-yl) 6-Me-Pyridin-3-yl364.451 365 30 F 4-NMe2-Ph 6-Me-Pyridin-3-yl 372.43 373 31 C(CH2)3(4-Et-Piperazin-1-yl) 4-F-Ph 410.494 411 32 C N-Me-Piperidin-4-yl4-F-Ph 353.399 354 33 C N-Me-Piperidin-4-yl 2,3,4-tri-F-Ph 389.379 39034 C (CH2)3NMe2 Ph 323.398 324 35 C (CH2)3NMe2 2,3-di-F-Ph 359.378 36036 C (CH2)3NMe2 6-Me-Pyridin-3-yl 338.413 339 37 D[4-[CH2(Pyrrolidin-1-yl)]-Ph] 4-F-Ph 415.47 416 38 C N-Me-Piperidin-4-yl5-Ph-Pyridin-3-yl 412.495 413 39 C (CH2)3(Pyrrolidin-1-yl) 2,3-di-F-Ph385.416 386 40 C [4-[CH2(Pyrrolidin-1-yl)]-Ph] 2,3-di-F-Ph 433.46 434 41C N-Me-Piperidin-4-yl Ph 335.409 336 42 C [4-[CH2(Pyrrolidin-1-yl)]-PhPh 397.48 398 43 C (CH2)3NMe2 4-F-Ph 341.388 342 44 C (CH2)3NMe25-Ph-Pyridin-3-yl 400.84 401 45 C (CH2)3(4-Et-Piperazin-1-yl)5-Ph-Pyridin-3-yl 469.59 470 46 C (CH2)3NMe2 Quinolin-3-yl 374.446 37547 C (CH2)3(4-Et-Piperazin-1-yl) Quinolin-3-yl 443.552 444 48 CN-Me-Piperidin-4-yl Quinolin-3-yl 386.457 387 49 D[4-[CH2(Pyrrolidin-1-yl)]-Ph] 5-Ph-Pyridin-3-yl 474.565 475 50 Fcyc-Pentyl 5-Ph-Pyridin-3-yl 383.453 384

1. A compound of formula (I):

or a derivative thereof, wherein; R¹ is unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted cycloalkenyl,unsubstituted or substituted aryl, aralkyl wherein the aryl and thealkyl moieties may each independently be unsubstituted or substituted,aralkenyl wherein the aryl and alkenyl moieties may each independentlybe unsubstituted or substituted, unsubstituted or substitutedheterocyclyl, or heterocyclylalkyl wherein the heterocyclyl and thealkyl moieties may each independently be unsubstituted or substituted;and R² is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl.
 2. A compound of formula (I) or a derivativethereof wherein R¹ is unsubstituted or substituted alkyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substituted aryl,unsubstituted or substituted heterocyclyl, or heterocyclylalkyl whereinthe heterocyclyl and the alkyl moieties may each independently beunsubstituted or substituted; and wherein R² is unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl.
 3. Acompound of formula (IA),

or a derivative thereof, wherein; R¹ is C₁₋₆ alkyl, cyclo₃₋₈ alkyl,di(C₁₋₆ alkyl)aminoalkyl, phenyl optionally substituted by di(C₁₋₆alkyl)amino, heterocyclyl wherein the heterocyclyl moiety may beoptionally substituted by C₁₋₆ alkyl and heterocyclylC₁₋₆ alkyl whereinthe heterocyclyl moiety may be optionally substituted by C1-6 alkyl andphenyl; and R² is phenyl optionally substituted by one or more haloatoms, quinolinyl and pyridinyl optionally susbtituted by C₁₋₆ alkyl,C₁₋₆ alkoxy and phenyl.
 4. A compound of formula (I), as claimed inclaim 1, wherein R¹ is n-propyl, iso-propyl, cyclopropyl, cyclopentyl,3-dimethylamninopropyl, 4-dimethylaminophenyl,3-(pyrrolidin-1-yl)propyl, 3-(piperidin- 1-yl)propyl,3-(4-ethylpiperazin- 1-yl)propyl, 1-methylpiperidin-4-yl and4-[(pyrrolidin-1-yl)methyl]phenyl and wherein R² is as defined inclaim
 1. 5. A compound of formula (I), as claimed in claim 1, wherein R¹is as defined in claim 1 and wherein R² is phenyl, 2-chlorophenyl,2,3-difluorophenyl, 4-fluorophenyl, 2,3,4-trifluorophenyl, pyridin-3-yl,5-phenylpyridin-3-yl, 6-methylpyridin-3-yl, 6-methyoxypyridin-3-yl andquinolin-3-yl.
 6. A compound of formula (I), as claimed in claim 1,wherein R¹ is n-propyl, iso-propyl, cyclopropyl, cyclopentyl,3-dimethylaminopropyl, 4-dimethylaminophenyl, 3-(pyrrolidin-1-yl)propyl,3-(piperidin-1-yl)propyl, 3-(4-ethylpiperazin-1-yl)propyl,1-methylpiperidin-4-yl and 4-[(pyrrolidin-1-yl)methyl]phenyl and whereinR² is phenyl, 2-chlorophenyl, 2,3-difluorophenyl, 4-fluorophenyl,2,3,4-trifluorophenyl, pyridin-3-yl, 5-phenylpyridin-3-yl,6-methylpyridin-3-yl, 6-methoxypyridin-3-yl and quinolin-3-yl.
 7. Apharmaceutical composition which comprises a compound of formula (I) asclaimed in any of claims 1 to 6 or a pharmaceutically acceptablederivative thereof, and a pharmaceutically acceptable carrier.
 8. Aprocess for the preparation of a compound of formula (I) as claimed inclaim 1 or a derivative thereof, which process comprises reaction of acompound of formula (II),

wherein; R² is as defined in formula (I), with a compound of formula(III),

wherein; R¹ is as defined in formula (I) and X is a leaving group, andthereafter, if required, carrying out one or more of the followingoptional steps: (i) converting a compound of formula (I) to a furthercompound of formula (I); (ii) removing any necessary protecting group;(iii) preparing an appropriate derivative of the compound so formed. 9.A process for the preparation of a compound of formula (I) as claimed inclaim 1 or a derivative thereof, which process comprises reaction of acompound of formula (V),

wherein; R¹ and R² are as defined in formula (I), with a nucleophile,and thereafter, if required, carrying out one or more of the followingoptional steps: (i) converting a compound of formula (I) to a furthercompound of formula (I); (ii) removing any necessary protecting group;(iii) preparing an appropriate derivative of the compound so formed. 10.A compound according to any of claims 1 to 6 or a formulation accordingto claim 7 for use in therapy.
 11. Use of a compound according to any ofclaims 1 to 6 for the manufacture of a medicament for the treatment ofconditions associated with a need for the inhibition of GSK-3.
 12. Useaccording to claim 11 wherein the condition associated with a need forthe inhibition of GSK-3 is selected from the group consisting ofdiabetes, conditions associated with diabetes, chronic neurodegenerativeconditions including dementias such as Alzheimer's disease, Parkinson'sdisease, progressive supranuclear palsy, subacute sclerosingpanencephalitic parkinsonism, postencephalitic parkinsonism, pugilisticencephalitis, guam parkinsonism-dementia complex, Pick's disease,corticobasal degeneration, frontotemporal dementia, Huntingdon'sdisease, AIDS associated dementia, amyotrophic lateral sclerosis,multiple sclerosis and neurotraumatic diseases such as acute stroke,mood disorders such as schizophrenia and bipolar disorders, promotion offunctional recovery post stroke, cerebral bleeding (for example, due tosolitary cerebral amyloid angiopathy), hair loss, obesity,atherosclerotic cardiovascular disease, hypertension, polycystic ovarysyndrome, syndrome X, ischaemia, traumatic brain injury, cancer,leulcopenia, Down's syndrome, Lewy body disease, inflammation, andimmunodeficiency.
 13. A method for the treatment of conditionsassociated with a need for inhibition of GSK-3 which method comprisesthe administration of a pharmaceutically effective, non-toxic amount ofa compound of formula (I) as claimed in any of claims 1 to 6 or apharmaceutically acceptable derivative thereof.
 14. A method accordingto claim 13 wherein the condition associated with a need for theinhibition of GSK-3 is selected from the group consisting of diabetes,conditions associated with diabetes, chronic neurodegenerativeconditions including dementias such as Alzheimer's disease, Parkinson'sdisease, progressive supranuclear palsy, subacute sclerosingpanencephalitic parkinsonism, postencephalitic parkinsonism, pugilisticencephalitis, guam parkinsonism-dementia complex, Pick's disease,corticobasal degeneration, frontotemporal dementia, Huntingdon'sdisease, AIDS associated dementia, amyotrophic lateral sclerosis,multiple sclerosis and neurotraumatic diseases such as acute stroke,mood disorders such as schizophrenia and bipolar disorders, promotion offunctional recovery post stroke, cerebral bleeding (for example, due tosolitary cerebral amyloid angiopathy), hair loss, obesity,atherosclerotic cardiovascular disease, hypertension, polycystic ovarysyndrome, syndrome X, ischaemia, traumatic brain injury, cancer,leukopenia, Down's syndrome, Lewy body disease, inflammation, andimmunodeficiency.
 15. A compound of formula (II),

wherein R² is as defined in formula (I)
 16. A compound of formula (V),

wherein R¹ and R² are as defined in formula (I).